The influence of cell context on the selection pressure for p53 mutation in human cancer.
Although p53 mutation is, overall, by far the most frequent somatic genetic abnormality in human cancer, in some common tumour types, notably carcinoma of breast, it is seen only in a phenotypically-distinct sub-set of cases, often correlated with adverse prognosis. Conventionally, this is viewed as the consequence of random differences in acquired genetic events acting on a common cell. Here we develop a fundamentally different hypothesis, which proposes that the liability of a given tumour to exhibit p53 mutation is predetermined by the nature of its cell of origin and, more specifically, depends on the extent to which wild-type p53 forms a rate-limiting step in the control of proliferative lifespan in that cell. In other words, the phenotype of the cell of origin constrains both tumour phenotype and 'choice' of genetic events. This concept can be extended to tumour progression, where evidence particularly from thyroid tumorigenesis suggests that a switch in differentiation state can play a major causal role in tumour evolution by altering the selection pressure for p53 mutation. Finally, analysis of transformed thyroid cells has also revealed a novel physiological mechanism by which growth suppression by wild-type p53 may be evaded in cell types whose lifespan control is p53-independent.
Wynford-Thomas
D
D
Cancer Research Campaign Laboratories, Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Blaydes
J
J
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D016922:Cellular Senescence; D005260:Female; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D013964:Thyroid Neoplasms / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D016159:Tumor Suppressor Protein p53